Activation of NAD(P)H: quinone oxidoreductase ameliorates spontaneous hypertension in an animal model via modulation of eNOS activity

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Title
Activation of NAD(P)H: quinone oxidoreductase ameliorates spontaneous hypertension in an animal model via modulation of eNOS activity
Author(s)
Yong Hoon KimJung Hwan HwangJung Ran Noh; Gil Tae Gang; D H Kim; H Y Son; T H Kwak; M Shong; I K Lee; Chul Ho Lee
Bibliographic Citation
Cardiovascular Research, vol. 91, no. 3, pp. 519-527
Publication Year
2011
Abstract
Aims Hypertension is one of the most common human diseases worldwide, and extensive research efforts are focused upon the identification and utilizing of novel therapeutic drug targets. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is an important regulator of blood pressure (BP). β-Lapachone (βL), a well-known substrate of NAD(P)H:quinone oxidoreductase (NQO1), increases the cellular NAD+/NADH ratio via the activation of NQO1. In this study, we evaluated whether βL-induced activation of NQO1 modulates BP in an animal model of hypertension. Methods and results Spontaneously hypertensive rats (SHR), primary human aortic endothelial cells (HAEC), and endothelial cell lines were used to investigate the hypotensive effect of βL and its mode of action. βL treatment stimulated endothelium-dependent vascular relaxation in response to acetylcholine in aorta of SHR and dramatically lowered BP in SHR, but the hypotensive effect was completely blocked by eNOS inhibition withnitro-l-arginine methyl ester. Aortic eNOS phosphorylation and eNOS protein expression were significantly increased in βL-treated SHR. In vitro studies revealed that βL treatment elevated the intracellular NAD+/NADH ratio and concentration of free Ca2+ ([Ca2+]i), and resulted in Akt/AMP-activated protein kinase/eNOS activation. These effects were abolished by NQO1 siRNA and [Ca2+]i inhibition through a ryanodine receptor blockade. Conclusion This study is the first to demonstrate that NQO1 activation has a hypotensive effect mediated by eNOS activation via cellular NAD+/NADH ratio modulation in an animal model. These results provide strong evidence suggesting NQO1 might be a new therapeutic target for hypertension.
Keyword
β-LapachoneeNOSHypertensionNAD+/NADH ratioNQO1
ISSN
0008-6363
Publisher
Oxford Univ Press
DOI
http://dx.doi.org/10.1093/cvr/cvr110
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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